{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:26:46Z","timestamp":1790076406753,"version":"4.0.1"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2018,7,10]],"date-time":"2018-07-10T00:00:00Z","timestamp":1531180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T00:00:00Z","timestamp":1536105600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM123609"],"award-info":[{"award-number":["R01GM123609"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["P20 RR030360"],"award-info":[{"award-number":["P20 RR030360"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2018,9,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The bacterial intracellular second messenger, cyclic dimeric GMP (c-di-GMP), regulates biofilm formation for many bacteria. The binding of c-di-GMP by the inner membrane protein LapD controls biofilm formation, and the LapD receptor is central to a complex network of c-di-GMP-mediated biofilm formation. In this study, we examine how c-di-GMP signaling specificity by a diguanylate cyclase (DGC), GcbC, is achieved via interactions with the LapD receptor and by small ligand sensing via GcbC\u2019s\n                    <jats:underline>ca<\/jats:underline>\n                    lcium channel\n                    <jats:underline>che<\/jats:underline>\n                    motaxis (CACHE) domain. We provide evidence that biofilm formation is stimulated by the environmentally relevant organic acid citrate (and a related compound, isocitrate) in a GcbC-dependent manner through enhanced GcbC-LapD interaction, which results in increased LapA localization to the cell surface. Furthermore, GcbC shows little ability to synthesize c-di-GMP in isolation. However, when LapD is present, GcbC activity is significantly enhanced (~8-fold), indicating that engaging the LapD receptor stimulates the activity of this DGC; citrate-enhanced GcbC-LapD interaction further stimulates c-di-GMP synthesis. We propose that the I-site of GcbC serves two roles beyond allosteric control of this enzyme: promoting GcbC-LapD interaction and stabilizing the active conformation of GcbC in the GcbC-LapD complex. Finally, given that LapD can interact with a dozen different DGCs of\n                    <jats:named-content content-type=\"genus-species\">Pseudomonas\u00a0fluorescens<\/jats:named-content>\n                    , many of which have ligand-binding domains, the ligand-mediated enhanced signaling via LapD-GcbC interaction described here is likely a conserved mechanism of signaling in this network. Consistent with this idea, we identify a second example of ligand-mediated enhancement of DGC-LapD interaction that promotes biofilm formation.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    In many bacteria, dozens of enzymes produce the dinucleotide signal c-di-GMP; however, it is unclear how undesired cross talk is mitigated in the context of this soluble signal and how c-di-GMP signaling is regulated by environmental inputs. We demonstrate that GcbC, a DGC, shows little ability to synthesize c-di-GMP in the absence of its cognate receptor LapD; GcbC-LapD interaction enhances c-di-GMP synthesis by GcbC, likely mediated by the I-site of GcbC. We further show evidence for a ligand-mediated mechanism of signaling specificity via increased physical interaction of a DGC with its cognate receptor. We envision a scenario wherein a \u201ccloud\u201d of weakly active DGCs can increase their activity by specific interaction with their receptor in response to appropriate environmental signals, concomitantly boosting c-di-GMP production, ligand-specific signaling, and biofilm formation.\n                  <\/jats:p>","DOI":"10.1128\/mbio.01254-18","type":"journal-article","created":{"date-parts":[[2018,7,9]],"date-time":"2018-07-09T06:44:50Z","timestamp":1531118690000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":55,"title":["Ligand-Mediated Biofilm Formation via Enhanced Physical Interaction between a Diguanylate Cyclase and Its Receptor"],"prefix":"10.1128","volume":"9","author":[{"given":"David","family":"Giacalone","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. Jarrod","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan J.","family":"Collins","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2211-6234","authenticated-orcid":false,"given":"Holger","family":"Sondermann","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori J.","family":"Koziol","sequence":"additional","affiliation":[{"name":"Department of Biology, New England College, Henniker, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2861-4392","authenticated-orcid":false,"given":"George A.","family":"O\u2019Toole","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1998.00797.x"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01780-05"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2005.04697.x"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00196-16"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/325279a0"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00585-07"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05539.x"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01287-13"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2003.03615.x"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808933106"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000588"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01978-15"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00090-16"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-micro-090816-093325"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(00)01672-8"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004862"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2012.08109.x"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaa1796"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2010.04.049"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00703-17"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.05483-11"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep35198"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00183-10"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.21848"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1129"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1004356007312"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1094\/MPMI.2002.15.11.1173"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.00682-06"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004380050762"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.72.3.1910-1924.2006"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000587"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.10.5752"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.11.5857"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp940"},{"key":"e_1_3_3_36_2","volume-title":"R: a language and environment for statistical computing","author":"R Core Team","year":"2016","unstructured":"R Core Team. 2016. 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R Foundation for Statistical Computing, Vienna, Austria. https:\/\/www.R-project.org\/."}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.01254-18","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.01254-18","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T21:53:12Z","timestamp":1646689992000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.01254-18"}},"subtitle":[],"editor":[{"given":"Joanna B.","family":"Goldberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2018,9,5]]},"references-count":35,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2018,9,5]]}},"alternative-id":["10.1128\/mBio.01254-18"],"URL":"https:\/\/doi.org\/10.1128\/mbio.01254-18","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/212183","asserted-by":"object"}]},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,5]]},"assertion":[{"value":"2018-06-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-06-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-07-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01254-18"}}